Drug-Free Macromolecular Therapeutics

无药大分子治疗

• 批准号: 10304911
• 负责人: JINDRICH H. KOPECEK
• 金额: $ 34.19万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304911
• 关键词: Actins; Adhesions; Antibodies; Apoptosis; Apoptotic; B lymphoid malignancy; Binding; CD20 Antigens; Calcium; Caspase; Cell surface; Cells; Cessation of life; Chlorambucil; Chronic Lymphocytic Leukemia; Clinical; Complex; Cyclophosphamide; Cytoskeleton; Diagnosis; Disease; Disease Resistance; Doxorubicin; Ensure; Evaluation; Exposure to; FDA approved; Female; Follicular Lymphoma; Generations; Genes; Genetic; Goals; Half-Life; Heavy-Chain Immunoglobulins; Human; In Vitro; Induction of Apoptosis; Length; Lymphoma; Lymphoma cell; Lysosomes; MS4A1 gene; Mantle Cell Lymphoma; Mediating; Membrane Microdomains; Modeling; Modification; Molecular Conformation; Nanoconjugate; Non-Hodgkin' s Lymphoma; Oligonucleotides; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Pharmaceutical Preparations; Prednisone; Recurrent disease; Relapse; Resistance; Sampling; Serum Albumin; Somatic Mutation; Structure; System; Testing; Therapeutic; Time; Treatment Efficacy; Vertebral column; Vincristine; anti-CD20; base; chemotherapeutic agent; chemotherapy; crosslink; design; disulfide bond; drug efficacy; flexibility; improved; in vivo; in vivo evaluation; indexing; large cell Diffuse non-Hodgkin' s lymphoma; macromolecule; male; mutational status; neonatal Fc receptor; novel; novel drug class; novel strategies; novel therapeutics; patient subsets; prognostic; receptor; response; rituximab; thioether; tositumomab; translational potential; treatment strategy; tumor

Rituximab (RTX) and other anti-CD20 antibodies (ofatumumab and obinutuzumab (OBN)) dramatically improved treatment of Non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Alone or in combination with chemotherapy (e.g. R-CHOP, a combination with cyclophosphamide, doxorubicin, vincristine, and prednisone) they produced better clinical outcomes. However, relapses frequently occur with poor patient outcomes. In 2017 in the USA, there were an estimated 72,240 new cases of NHL and 20,140 deaths, 20,110 new cased of CLL and 4,660 deaths in both males and females. This demonstrates the need for improved treatment strategies. The goal of the proposed studies is to design, synthesize, and evaluate the second generation of drug-free macromolecular therapeutics (DFMT) for the treatment of B-cell malignancies. Anti-CD20 antibodies are divided into Type I such as RTX and Type II such as OBN; they have different patterns of binding to CD20 receptor. RTX binds between CD20 tetramers resulting in accumulation in lipid rafts, calcium influx and caspase activation. OBN binds within one tetramer with the conformation compatible with homotypic adhesion regions, leading to actin cytoskeleton remodeling and lysosome disruption. Our design enhances the activity of Type II OBN by triggering the apoptosis activation pathways of both types of antibodies. This new system is composed of two nanoconjugates: a) bispecific engager, OBN-MORF1 (OBN conjugated to one morpholino oligonucleotide MORF1); and b) a crosslinking (effector) component HSA- (MORF2)X (human serum albumin (HSA) grafted with multiple copies of complementary morpholino oligonucleotide 2). Modification of OBN with one MORF1 does not impact the binding of OBN-MORF1 to CD20 and following binding to CD20 Type II effects occur. Further exposure to multivalent effector HSA- (MORF2)X results in clustering the OBN-MORF1-CD20 complexes into lipid rafts and Type I effects occur. This new approach, called “clustered OBN (cOBN)” combines effects of both antibody types resulting in very high apoptotic levels. In the bispecific engager, MORF1 will be attached to OBN via thioether bond following reduction of OBN's disulfide bonds. The structure of the multivalent crosslinking effector HSA-(MORF2)x will be optimized to ensure the highest efficiency of the cOBN system on disseminated models of NHL. Recently, combination of OBN with chlorambucil was FDA approved. We have shown that HSA-based DFMT sensitizes NHL cells to different chemotherapeutic agents. Thus we plan to evaluate the impact of combining cOBN with chemotherapeutics on the mechanism and efficiency of apoptosis induction. Finally, we demonstrated efficacy of DFMT on resistant lymphomas and cells isolated from patients diagnosed with various subtypes of B cell malignancies. We shall identify subsets of patients that respond favorably to our new therapeutics. In summary, this proposal is scientifically novel and has great translational potential. Also, it provides a new paradigm for the design of macromolecular therapeutics applicable to other diseases beyond lymphomas.

利妥昔单抗 (RTX) 和其他抗 CD20 抗体（ofatumumab 和 obinutuzumab (OBN)）显着 改善非霍奇金淋巴瘤（NHL）和慢性淋巴细胞白血病（CLL）的治疗。单独或在 与化疗联合（例如 R-CHOP，与环磷酰胺、阿霉素、 长春新碱和泼尼松）它们产生了更好的临床结果。但经常会出现复发的情况 患者治疗效果不佳。 2017 年，美国估计有 72,240 例 NHL 新病例和 20,140 例 NHL 病例。 死亡人数，新增 CLL 病例 20,110 例，男性和女性死亡 4,660 例。这表明需要 以改善治疗策略。拟议研究的目标是设计、综合和评估 用于治疗 B 细胞恶性肿瘤的第二代无药大分子疗法 (DFMT)。 抗CD20抗体分为I型如RTX和II型如OBN；他们有不同的 与 CD20 受体的结合模式。 RTX 在 CD20 四聚体之间结合，导致脂质积累 筏、钙流入和半胱天冬酶激活。 OBN 结合在一个四聚体内，且构象兼容 具有同型粘附区域，导致肌动蛋白细胞骨架重塑和溶酶体破坏。我们的 设计通过触发两种类型的细胞凋亡激活途径来增强 II 型 OBN 的活性 抗体。这个新系统由两种纳米缀合物组成：a) 双特异性接合剂 OBN-MORF1 (OBN 缀合至一个吗啉代寡核苷酸MORF1)； b) 交联（效应）成分 HSA- (MORF2)X（人血清白蛋白 (HSA)，移植有多个互补吗啉代拷贝 寡核苷酸2)。用一个 MORF1 修饰 OBN 不会影响 OBN-MORF1 与 CD20 以及与 CD20 结合后发生 II 型效应。进一步暴露于多价效应子 HSA- (MORF2)X 导致 OBN-MORF1-CD20 复合物聚集成脂筏并发生 I 型效应。 这种新方法称为“簇状 OBN (cOBN)”，结合了两种抗体类型的作用，从而产生非常好的效果。 高凋亡水平。在双特异性接合剂中，MORF1 将通过硫醚键连接到 OBN，如下 OBN二硫键的还原。多价交联效应子 HSA-(MORF2)x 的结构将 进行优化，以确保 cOBN 系统在 NHL 传播模型上的最高效率。最近， OBN 与苯丁酸氮芥的组合已获得 FDA 批准。我们已经证明基于 HSA 的 DFMT 具有敏感性 NHL 细胞针对不同的化疗药物。因此，我们计划评估将 cOBN 与 化疗对细胞凋亡诱导机制和效率的影响。最后我们演示了 DFMT 对耐药性淋巴瘤和从诊断为各种亚型的患者中分离的细胞的疗效 B细胞恶性肿瘤。我们将确定对我们的新疗法有良好反应的患者亚群。在 总之，该提议具有科学新颖性，具有巨大的转化潜力。此外，它还提供了一种新的 适用于淋巴瘤以外其他疾病的大分子疗法的设计范例。